tbuckley/cabot-search huggingface dataset:
Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability
Authors: Ya-Li Sang, Christophe Pannecouque, Erik De Clercq, Shuai Wang, Fen-Er Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Considering the undesirable metabolic stability of our recently identified NNRTI 5 (t1/2 = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes (t1/2 = 2754 min), which was about 29-fold longer than that of 5 (t1/2 = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC50 = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC50 = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound 9g was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.
A Self-Propagating c-Met–SOX2 Axis Drives Cancer-Derived IgG Signaling That Promotes Lung Cancer Cell Stemness
Authors: Xinmei Huang, Shenghua Zhang, Jingshu Tang, Tian Tian, Yilin Pan, Lina Wu, Jingxuan Zhang, Yang Liu, Jing Huang, Hui Dai, Weiyan Xu, Youhui Zhang, Jinfeng Chen, Mengshu Cao, Liang Zhang, Xiaoyan Qiu
Journal: Cancer Research (2023)

Sialylated cancer IgG activates c-Met-SOX2 signaling to promote stemness properties in cancer cells and can be targeted to suppress tumor growth.
A standardized framework for risk-based assessment of treatment effect heterogeneity in observational healthcare databases
Authors: Alexandros Rekkas, David van Klaveren, Patrick B. Ryan, Ewout W. Steyerberg, David M. Kent, Peter R. Rijnbeek
Journal: npj Digital Medicine (2023)

Abstract Treatment effects are often anticipated to vary across groups of patients with different baseline risk. The Predictive Approaches to Treatment Effect Heterogeneity (PATH) statement focused on baseline risk as a robust predictor of treatment effect and provided guidance on risk-based assessment of treatment effect heterogeneity in a randomized controlled trial. The aim of this study is to extend this approach to the observational setting using a standardized scalable framework. The proposed framework consists of five steps: (1) definition of the research aim, i.e., the population, the treatment, the comparator and the outcome(s) of interest; (2) identification of relevant databases; (3) development of a prediction model for the outcome(s) of interest; (4) estimation of relative and absolute treatment effect within strata of predicted risk, after adjusting for observed confounding; (5) presentation of the results. We demonstrate our framework by evaluating heterogeneity of the effect of thiazide or thiazide-like diuretics versus angiotensin-converting enzyme inhibitors on three efficacy and nine safety outcomes across three observational databases. We provide a publicly available R software package for applying this framework to any database mapped to the Observational Medical Outcomes Partnership Common Data Model. In our demonstration, patients at low risk of acute myocardial infarction receive negligible absolute benefits for all three efficacy outcomes, though they are more pronounced in the highest risk group, especially for acute myocardial infarction. Our framework allows for the evaluation of differential treatment effects across risk strata, which offers the opportunity to consider the benefit-harm trade-off between alternative treatments.
P450-mediated dehydrotyrosine formation during WS9326 biosynthesis proceeds via dehydrogenation of a specific acylated dipeptide substrate
Authors: Songya Zhang, Lin Zhang, Anja Greule, Julien Tailhades, Edward Marschall, Panward Prasongpholchai, Daniel J. Leng, Jingfan Zhang, Jing Zhu, Joe A. Kaczmarski, Ralf B. Schittenhelm, Oliver Einsle, Colin J. Jackson, Fabrizio Alberti, Andreas Bechthold, Youming Zhang, Manuela Tosin, Tong Si, Max J. Cryle
Journal: Acta Pharmaceutica Sinica B (2023)

WS9326A is a peptide antibiotic containing a highly unusual N-methyl-E-2-3-dehydrotyrosine (NMet-Dht) residue that is incorporated during peptide assembly on a non-ribosomal peptide synthetase (NRPS). The cytochrome P450 encoded by sas16 (P450Sas) has been shown to be essential for the formation of the alkene moiety in NMet-Dht, but the timing and mechanism of the P450Sas-mediated α,β-dehydrogenation of Dht remained unclear. Here, we show that the substrate of P450Sas is the NRPS-associated peptidyl carrier protein (PCP)-bound dipeptide intermediate (Z)-2-pent-1'-enyl-cinnamoyl-Thr-N-Me-Tyr. We demonstrate that P450Sas-mediated incorporation of the double bond follows N-methylation of the Tyr by the N-methyl transferase domain found within the NRPS, and further that P450Sas appears to be specific for substrates containing the (Z)-2-pent-1'-enyl-cinnamoyl group. A crystal structure of P450Sas reveals differences between P450Sas and other P450s involved in the modification of NRPS-associated substrates, including the substitution of the canonical active site alcohol residue with a phenylalanine (F250), which in turn is critical to P450Sas activity and WS9326A biosynthesis. Together, our results suggest that P450Sas catalyses the direct dehydrogenation of the NRPS-bound dipeptide substrate, thus expanding the repertoire of P450 enzymes that can be used to produce biologically active peptides.
Probabilistic Points of Departure and Reference Doses for Characterizing Human Noncancer and Developmental/Reproductive Effects for 10,145 Chemicals
Authors: Nicolò Aurisano, Olivier Jolliet, Weihsueh A. Chiu, Richard Judson, Suji Jang, Aswani Unnikrishnan, Marissa B. Kosnik, Peter Fantke
Journal: Environmental Health Perspectives (2023)

Background: Regulatory toxicity values used to assess and manage chemical risks rely on the determination of the point of departure (POD) for a critical effect, which results from a comprehensive and systematic assessment of available toxicity studies. However, regulatory assessments are only available for a small fraction of chemicals. Objectives: Using in vivo experimental animal data from the U.S. Environmental Protection Agency's Toxicity Value Database, we developed a semiautomated approach to determine surrogate oral route PODs, and corresponding toxicity values where regulatory assessments are unavailable. Methods: We developed a curated data set restricted to effect levels, exposure routes, study designs, and species relevant for deriving toxicity values. Effect levels were adjusted to chronic human equivalent benchmark doses (BMDh). We hypothesized that a quantile of the BMDh distribution could serve as a surrogate POD and determined the appropriate quantile by calibration to regulatory PODs. Finally, we characterized uncertainties around the surrogate PODs from intra- and interstudy variability and derived probabilistic toxicity values using a standardized workflow. Results: The BMDh distribution for each chemical was adequately fit by a lognormal distribution, and the 25th percentile best predicted the available regulatory PODs [R2≥0.78, residual standard error (RSE)≤0.53 log10 units]. We derived surrogate PODs for 10,145 chemicals from the curated data set, differentiating between general noncancer and reproductive/developmental effects, with typical uncertainties (at 95% confidence) of a factor of 10 and 12, respectively. From these PODs, probabilistic reference doses (1% incidence at 95% confidence), as well as human population effect doses (10% incidence), were derived. Discussion: In providing surrogate PODs calibrated to regulatory values and deriving corresponding toxicity values, we have substantially expanded the coverage of chemicals from 744 to 8,023 for general noncancer effects, and from 41 to 6,697 for reproductive/developmental effects. These results can be used across various risk assessment and risk management contexts, from hazardous site and life cycle impact assessments to chemical prioritization and substitution. https://doi.org/10.1289/EHP11524
Changes in Medicare Accountable Care Organization Spending, Utilization, and Quality Performance 2 Years Into the COVID-19 Pandemic
Authors: Brandon W. Yan, Maya Shashoua, Jose F. Figueroa
Journal: JAMA Network Open (2023)

This cohort study uses data from the Medicare Shared Savings Program to assess changes in spending, utilization, and quality performance from before the COVID-19 pandemic (2019) to year 2 of the pandemic (2021).
Minimally invasive bioprinting for in situ liver regeneration
Authors: Yueying Yang, Zhengyang Yu, Xiaohuan Lu, Jiahao Dai, Cheng Zhou, Jing Yan, Lin Wang, Zheng Wang, Jianfeng Zang
Journal: Bioactive Materials (2023)

In situ bioprinting is promising for developing scaffolds directly on defect models in operating rooms, which provides a new strategy for in situ tissue regeneration. However, due to the limitation of existing in situ biofabrication technologies including printing depth and suitable bioinks, bioprinting scaffolds in deep dermal or extremity injuries remains a grand challenge. Here, we present an in vivo scaffold fabrication approach by minimally invasive bioprinting electroactive hydrogel scaffolds to promote in situ tissue regeneration. The minimally invasive bioprinting system consists of a ferromagnetic soft catheter robot for extrusion, a digital laparoscope for in situ monitoring, and a Veress needle for establishing a pneumoperitoneum. After 3D reconstruction of the defects with computed tomography, electroactive hydrogel scaffolds are printed within partial liver resection of live rats, and in situ tissue regeneration is achieved by promoting the proliferation, migration, and differentiation of cells and maintaining liver function in vivo.
<i>Helicobacter pylori</i> , Homologous-Recombination Genes, and Gastric Cancer
Authors: Yoshiaki Usui, Yukari Taniyama, Mikiko Endo, Yuriko N. Koyanagi, Yumiko Kasugai, Isao Oze, Hidemi Ito, Issei Imoto, Tsutomu Tanaka, Masahiro Tajika, Yasumasa Niwa, Yusuke Iwasaki, Tomomi Aoi, Nozomi Hakozaki, Sadaaki Takata, Kunihiko Suzuki, Chikashi Terao, Masanori Hatakeyama, Makoto Hirata, Kokichi Sugano, Teruhiko Yoshida, Yoichiro Kamatani, Hidewaki Nakagawa, Koichi Matsuda, Yoshinori Murakami, Amanda B. Spurdle, Keitaro Matsuo, Yukihide Momozawa
Journal: New England Journal of Medicine (2023)

Helicobacter pylori infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated.We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).Germline pathogenic variants in nine genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) were associated with the risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P = 0.02). At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6]).H. pylori infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.).
Prophylactic Antibiotics for Vaginal Delivery — Benefits and Possible Harms
Authors: Jeanne S. Sheffield
Journal: New England Journal of Medicine (2023)

Ignaz Semmelweis, a Hungarian physician often labeled the "Savior of Women," pioneered the use of antiseptic techniques to decrease puerperal fever. Although his seminal 1861 publication, The Etiology, Concept and Prophylaxis of Childbed Fever, was poorly received at the time, it is now the foundation for contemporary preventative obstetric practices, including routine hand washing. Despite this progress, maternal infection remains one of the top causes of maternal death worldwide and is currently ranked third behind hypertension and hemorrhage. The World Health Organization (WHO) has reported that as of 2017, approximately 810 women died each day from preventable causes related to . . .
Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia
Authors: Zhenhua Chen, Keren Zhou, Jianhuang Xue, Andrew Small, Gang Xiao, Le Xuan Truong Nguyen, Zheng Zhang, Emily Prince, Hengyou Weng, Huilin Huang, Zhicong Zhao, Ying Qing, Chao Shen, Wei Li, Li Han, Brandon Tan, Rui Su, Hanjun Qin, Yangchan Li, Dong Wu, Zhaohui Gu, Vu N. Ngo, Xin He, Jianfei Chao, Keith Leung, Kitty Wang, Lei Dong, Xi Qin, Zhenming Cai, Yue Sheng, Yu Chen, Xiwei Wu, Bin Zhang, Yanhong Shi, Guido Marcucci, Zhijian Qian, Mingjiang Xu, Markus Müschen, Jianjun Chen, Xiaolan Deng
Journal: Science Translational Medicine (2023)

Although the overall survival rate of B cell acute lymphoblastic leukemia (B-ALL) in childhood is more than 80%, it is merely 30% in refractory/relapsed and adult patients with B-ALL. This demonstrates a need for improved therapy targeting this subgroup of B-ALL. Here, we show that the ten-eleven translocation 1 (TET1) protein, a dioxygenase involved in DNA demethylation, is overexpressed and plays a crucial oncogenic role independent of its catalytic activity in B-ALL. Consistent with its oncogenic role in B-ALL, overexpression of TET1 alone in normal precursor B cells is sufficient to transform the cells and cause B-ALL in mice within 3 to 4 months. We found that TET1 protein is stabilized and overexpressed because of its phosphorylation mediated by protein kinase C epsilon (PRKCE) and ATM serine/threonine kinase (ATM), which are also overexpressed in B-ALL. Mechanistically, TET1 recruits STAT5B to the promoters of CD72 and JCHAIN and promotes their transcription, which in turn promotes B-ALL development. Destabilization of TET1 protein by treatment with PKC or ATM inhibitors (staurosporine or AZD0156; both tested in clinical trials), or by pharmacological targeting of STAT5B, greatly decreases B-ALL cell viability and inhibits B-ALL progression in vitro and in vivo. The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL.
Can Molecular Imaging Find a Path to Navigate Evolving Breast Cancer Treatments?
Authors: Hannah M. Linden, David A. Mankoff
Journal: Clinical Cancer Research (2023)

[18F]fluoroestradiol (FES) PET is an FDA-approved imaging biomarker. Like IHC, FES positivity predicts clinical benefit of endocrine therapy. In addition, FES measures the target activity in endocrine agent drug development. A recent study found that whole body tumor heterogeneity of expression predicts clinical benefit, and serial FES monitors estrogen receptor blockade and posttreatment release. See related article by Iqbal et al., p. 2075.
Instructional materials that control cellular activity through synthetic Notch receptors
Authors: Joanne C. Lee, Hannah J. Brien, Bonnie L. Walton, Zachary M. Eidman, Satoshi Toda, Wendell A. Lim, Jonathan M. Brunger
Journal: Biomaterials (2023)

The field of regenerative engineering relies primarily on the dual technical platforms of cell selection/conditioning and biomaterial fabrication to support directed cell differentiation. As the field has matured, an appreciation for the influence of biomaterials on cell behaviors has resulted in engineered matrices that meet biomechanical and biochemical demands of target pathologies. Yet, despite advances in methods to produce designer matrices, regenerative engineers remain unable to reliably orchestrate behaviors of therapeutic cells in situ. Here, we present a platform named MATRIX whereby cellular responses to biomaterials can be custom defined by combining engineered materials with cells expressing cognate synthetic biology control modules. Such privileged channels of material-to-cell communication can activate synthetic Notch receptors and govern activities as diverse as transcriptome engineering, inflammation attenuation, and pluripotent stem cell differentiation, all in response to materials decorated with otherwise bioinert ligands. Further, we show that engineered cellular behaviors are confined to programmed biomaterial surfaces, highlighting the potential to use this platform to spatially organize cellular responses to bulk, soluble factors. This integrated approach of co-engineering cells and biomaterials for orthogonal interactions opens new avenues for reproducible control of cell-based therapies and tissue replacements.
Patient Beliefs About Antibiotics for Appendicitis and Outcomes—Reply
Authors: Irene Y. Zhang, Emily C. Voldal, David R. Flum
Journal: JAMA Surgery (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
An adversarial training framework for mitigating algorithmic biases in clinical machine learning
Authors: Jenny Yang, Andrew A. S. Soltan, David W. Eyre, Yang Yang, David A. Clifton
Journal: npj Digital Medicine (2023)

Machine learning is becoming increasingly prominent in healthcare. Although its benefits are clear, growing attention is being given to how these tools may exacerbate existing biases and disparities. In this study, we introduce an adversarial training framework that is capable of mitigating biases that may have been acquired through data collection. We demonstrate this proposed framework on the real-world task of rapidly predicting COVID-19, and focus on mitigating site-specific (hospital) and demographic (ethnicity) biases. Using the statistical definition of equalized odds, we show that adversarial training improves outcome fairness, while still achieving clinically-effective screening performances (negative predictive values >0.98). We compare our method to previous benchmarks, and perform prospective and external validation across four independent hospital cohorts. Our method can be generalized to any outcomes, models, and definitions of fairness.
Therapeutic neutralizing monoclonal antibody administration protects against lethal yellow fever virus infection
Authors: Michael J. Ricciardi, Lauren N. Rust, Nuria Pedreño-Lopez, Sofiya Yusova, Sreya Biswas, Gabriela M. Webb, Lucas Gonzalez-Nieto, Thomas B. Voigt, Johan J. Louw, Fernanda D. Laurino, John R. DiBello, Hans-Peter Raué, Aaron M. Barber-Axthelm, Kimberly Chun, Samantha Uttke, Lidiane M. S. Raphael, Aaron Yrizarry-Medina, Brandon C. Rosen, Rebecca Agnor, Lina Gao, Caralyn Labriola, Michael Axthelm, Jeremy Smedley, Justin G. Julander, Myrna C. Bonaldo, Laura M. Walker, Ilhem Messaoudi, Mark K. Slifka, Dennis R. Burton, Esper G. Kallas, Jonah B. Sacha, David I. Watkins, Benjamin J. Burwitz
Journal: Science Translational Medicine (2023)

Yellow fever virus (YFV) is a reemerging global health threat, driven by several factors, including increased spread of the mosquito vector and rapid urbanization. Although a prophylactic vaccine exists, vaccine hesitancy, supply deficits, and distribution difficulties leave specific populations at risk of severe YFV disease, as evidenced by recent outbreaks in South America. To establish a treatment for patients with severe YFV infection, we tested 37 YFV-specific monoclonal antibodies isolated from vaccinated humans and identified two capable of potently neutralizing multiple pathogenic primary YFV isolates. Using both hamster and nonhuman primate models of lethal YFV infection, we demonstrate that a single administration of either of these two potently neutralizing antibodies during acute infection fully controlled viremia and prevented severe disease and death in treated animals. Given the potential severity of YFV-induced disease, our results show that these antibodies could be effective in saving lives and fill a much-needed void in managing YFV cases during outbreaks.
Revumenib Appears Safe in Leukemia Trial, Yields Remission in Some
Authors: Emily Harris
Journal: JAMA (2023)

The US maternal mortality rate continued to increase in 2021, according to a new report from the National Center for Health Statistics.The trend predated the COVID-19 pandemic: between 2018 and 2019, the rate increased from 17.4 maternal deaths per 100 000 live births to 20.1.It then continued to rise to 23.8 in 2020 and to 32.9 in 2021.There were 1205 maternal deaths in 2021 compared with 658 in 2018.Disparities in maternal mortality also persisted in 2021, with 69.9 Black women dying per 100 000 live births-a 2.6 times higher rate than that of White women that year.For all racial and ethnic groups included in the analysis-Black, Hispanic, and White-the number of deaths per 100 000 live births increased every year from 2018 through 2021.The maternal mortality rate also increased substantially for women aged 40 years or older between 2020 to 2021, from about 107.9 deaths per 100 000 live births to 138.5.In 2019, the maternal mortality rate for this age group was 75.5, a decrease from 81.9 the year prior.
A Pinpoint Orifice on the Glans Penis of a Young Man
Authors: Catalina Hasbún, Ximena Wortsman, Jorge Navarrete
Journal: JAMA Dermatology (2023)

A man in his 30s presents with a 14-year history of purulent penile discharge that has not responded to antibiotics or corticosteroids. A pinpoint orifice is found on the glans penis. What is your diagnosis?